Alzheimer's disease (AD), a progressive neurodegenerative disorder which causes memory loss and dementia, is characterized by the presence of neuritic plaques and neurofibrillary tangles in select brain regions. Several observations suggest that pathology in entorhinal cortex play critical roles in the development of dementia. However, it is contentious whether tangles or plaques (and beta-amyloid deposits) in this region correlate with dementia. This proposal will examine the relationship between entorhinal pathology and cognitive function using data and tissues obtained from the Nun Study, a longitudinal study of aging in 678 Catholic Sisters. Preliminary studies demonstrate that both beta-amyloid load (% area occupied by beta-amyloid deposits) and neurofibrillary pathology in entorhinal cortex correlate with cognitive decline. The first specific aim will extend these observations, and examine specific beta-amyloid isoforms as well as the relationship between the beta-amyloid deposits and neurofibrillary pathology. The second specific aim will examine specific hypotheses regarding the relationship between plaques and tangles. Tangles contain paired helical filaments, composed of hyperphosphorylated tau. We predict that beta-amyloid itself does not cause tau hyperphosphorylation, but rather leads to tau dephosphorylation. Neuritic plaques are associated with activated microglia, which release cytokines including tumor necrosis factor and interleukin-1. These proinflammatory cytokines inhibit phosphatase activity in fibroblasts. This proposal will examine the hypothesis that TNFalpha and IL-1alpha mediate phosphatase inhibition which contributes to tau hyperphosphorylation in entorhinal neurons.